Obesity, Biomechanics, and Inflammation in Osteoarthritis

骨关节炎的肥胖、生物力学和炎症

• 批准号: 8641585
• 负责人: Farshid Guilak
• 金额: $ 31.74万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641585
• 关键词: Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Behavioral; Biological Markers; Biomechanics; Body Weight decreased; Body fat; Cartilage; Chondrocytes; Chronic; Collagen; Degenerative polyarthritis; Development; Diagnostic; Diet; Dietary Fatty Acid; Dietary Intervention; Disease; Elements; Event; Exhibits; Family suidae; Fatty Acids; Fatty acid glycerol esters; Gene Expression; Goals; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interleukin-1; Joint Instability; Joints; Knee Osteoarthritis; Lead; Leptin; Leptin deficiency; Ligaments; Link; Measures; Mechanical Stress; Mechanics; Medial meniscus structure; Mediator of activation protein; Meniscus structure of joint; Metabolism; Modeling; Molecular; Monounsaturated Fatty Acids; Morbid Obesity; Mus; Nonesterified Fatty Acids; Obese Mice; Obesity; Omega-3 Fatty Acids; Osteoarthrosis Deformans; Pain; Pathogenesis; Pathology; Play; Prevalence; Production; Protein Biosynthesis; Risk Factors; Role; Saturated Fatty Acids; Severities; Severity of illness; Signal Transduction; Testing; Tissues; United States; Unsaturated Fatty Acids; Weight Gain; adipokines; aggrecan; articular cartilage; base; cytokine; db/db mouse; feeding; improved; in vitro Model; in vivo; insight; joint injury; joint loading; lard; leptin receptor; mouse model; prevent; public health relevance; research study; weight loss intervention

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a painful and debilitating disease of the synovial joints, affecting an estimated 27 million people in the United States. As the prevalence of obesity has risen dramatically in the past two decades, we now know that obesity is likely to be the primary preventable risk factor for OA. The goal of this project is to examine the influence of dietary fatty acids on obesity-associated OA in mice, and to examine their interaction with altered biomechanical and pro-inflammatory cytokines using various in vivo and in vitro models. We propose that low-grade chronic systemic inflammation - due to obesity or pro- inflammatory fatty acids in the diet - acts in synergy with local inflammatory cytokines or altered mechanical loading following injury to promote a state of inflammation and matrix degradation in the articular cartilage. We will pursue the following aims: In Aim 1, we will examine the role of a high-fat lard- based diet in the development of OA in a leptin-receptor deficient mouse (db/db), and we will also measure osteoarthritic changes in diet-induced obese mice fed high-fat diets high in saturated and monounsaturated fatty acids, or omega-3 or omega-6 poly-unsaturated fatty acids. In Aim 2, we will examine the effects of obesity (via high-fat diet or leptin deficiency) and weight loss on the progression of OA in a destabilized medial meniscus model of mouse OA. In Aim 3, we will use controlled in vitro models of cartilage explant loading to examine the effects of mechanical stress in combination with pro- inflammatory cytokines and fatty acids on the anabolic and catabolic activities of the chondrocytes, as measured by biomarker production, gene expression, and protein synthesis of collagen II and aggrecan. Detailed studies of the interactions between specific biomechanical factors, pro-inflammatory mediators, and tissue metabolism in articular cartilage will improve our understanding of the pathology of the OA, particularly as it relates in vivo to "biomechanical" factors such as obesity, injury, or weight loss. The results of this study will provide new insight into key elements of the pathogenesis of OA, and ultimately could lead to new treatments that exploit physical, dietary, and molecular therapies to prevent disease.

描述(申请人提供)：骨关节炎(OA)是一种疼痛和衰弱的滑膜关节疾病，在美国估计有2700万人受到影响。随着肥胖症的流行在过去20年里急剧上升，我们现在知道肥胖很可能是骨性关节炎的主要可预防风险因素。本项目的目标是研究饮食脂肪酸对肥胖相关的小鼠骨关节炎的影响，并使用不同的体内和体外模型来研究它们与改变的生物力学和促炎细胞因子的相互作用。我们认为，由于肥胖或饮食中的致炎脂肪酸引起的轻度慢性全身炎症与局部炎症细胞因子或损伤后机械负荷的改变协同作用，促进了关节软骨的炎症和基质降解状态。我们将追求以下目标：在目标1中，我们将研究高脂肪猪油饮食在瘦素受体缺陷小鼠(db/db)发生骨性关节炎中的作用，我们还将测量饮食诱导的肥胖小鼠的骨关节炎变化，这些小鼠喂食高饱和和单不饱和脂肪酸，或omega-3或omega-6多不饱和脂肪酸。在目标2中，我们将研究肥胖(通过高脂饮食或瘦素缺乏)和体重减轻对内侧半月板失稳的小鼠骨性关节炎模型进展的影响。在目的3中，我们将使用软骨移植块负载的体外对照模型，通过生物标记物的产生、II型胶原和aggrecan的基因表达和蛋白质合成来检测机械应力与促炎细胞因子和脂肪酸对软骨细胞合成代谢和分解代谢活性的影响。详细研究关节软骨中特定的生物力学因素、促炎介质和组织代谢之间的相互作用将有助于我们更好地理解骨关节炎的病理机制，特别是当它与体内的“生物力学”因素，如肥胖、损伤或体重减轻有关时。这项研究的结果将为OA发病机制的关键因素提供新的见解，并最终可能导致利用物理、饮食和分子疗法来预防疾病的新疗法。